The ubiquinones, also commonly called coenzyme Qn(n=1-12), constitute essential cellular components of many life forms. In humans, CoQ10 is the predominant member of this class of polyprenoidal natural products and is well-known to function primarily as a redox carrier in the respiratory chain (Lenaz, Coenzyme Q. Biochemistry, Bioenergetics, and Clinical Applications of Ubiquinone, Wiley-Interscience: New York (1985); Trumpower, Function of Ubiquinones in Energy Conserving Systems, Academic Press, New York (1982); Thomson, R. H., Naturally Occurring Quinones, 3rd ed., Academic Press, New York (1987); Bliznakov et al., The Miracle Nutrient Coenzyme Q10, Bantom Books, New York (1987)).
Coenzyme Q plays an essential role in the orchestration of electron-transfer processes necessary for respiration. Almost all vertebrates rely on one or more forms of this series of compounds which are found in the mitrochondria of every cell (i.e., they are ubiquitous, hence the alternative name xe2x80x9cubiquinonesxe2x80x9d). Although usually occurring with up to 12 prenoidal units attached to a p-quinone headgroup, CoQ10 is the compound used by humans as a redox carrier. Oftentimes unappreciated is the fact that when less than normal levels are present, the body must construct its CoQ10 from lower forms obtained through the diet, and that at some point in everyone""s life span the efficiency of that machinery begins to drop. (Blizakov et al., supra) The consequences of this in vivo deterioration can be substantial; levels of CoQ10 have been correlated with increased sensitivity to infection (i.e., a weakening of the immune system), strength of heart muscle, and metabolic rates tied to energy levels and vigor. In some countries (e.g., Japan), CoQ10 is treated as a xe2x80x9cdrugxe2x80x9d, prescribed especially for those having suffered from heart disease, and is among the leading pharmaceuticals sold. In the United States, however, it is considered a dietary supplement, sold typically in health food stores or through mail order houses at reasonable prices. It is indeed fortunate that quantities of CoQ10 are available via well-established fermentation and extraction processes (e.g., Sasikala et al., Adv. Appl. Microbiol., 41:173 (1995); U.S. Pat. Nos. 4,447,362; 3,313,831; and 3,313,826) an apparently more cost-efficient route relative to total synthesis. However, for producing lower forms of CoQ, such processes are either far less efficient or are unknown. Thus, the costs of these materials for research purposes are astonishingly high, e.g., CoQ6 is xcx9c$22,000/g, and CoQ9 is over $40,000/g. (Sigma-Aldrich Catalog, Sigma-Aldrich: St. Louis, pp. 306-307 (1998)).
Several approaches to synthesizing the ubiquinones have been developed over the past 3-4 decades, attesting to the importance of these compounds. Recent contributions have invoked such varied approaches as Lewis acid-induced prenoidal stannane additions to quinones, (Naruta, J. Org. Chem., 45:4097 (1980)) reiterative Pd(0)-catalyzed couplings of doubly activated prenoidal chains with allylic carbonates bearing the required aromatic nucleus in protected form (Eren et al., J. Am. Chem. Soc., 110:4356 (1988) and references therein), and a Diels-Alder, retro Diels-Alder route to arrive at the quinone oxidation state directly (Van Lient et al., Rec. Trav. Chim. Pays-Bays 113:153 (1994); and Rxc3xcittiman et al., Helv. Chim. Acta, 73:790 (1990)). Nonetheless, all are lengthy, linear rather than convergent, and/or inefficient. Moreover, problems in controlling double bond stereochemistry using, e.g., a copper(I)-catalyzed allylic Grignard-allylic halide coupling can lead to complicated mixtures of geometrical isomers that are difficult to separate given the hydrocarbon nature of the side chains (Yanagisawa, et al., Synthesis, 1130 (1991)).
For the reasons set forth above, a convergent method for the synthesis of the ubiquinones and their analogues which originates with a simple benzenoid precursor and procedes with retention of the double bond stereochemistry would represent a significant advance in the synthesis of ubiquinones and their analogues. The present invention provides such a method and ubiquinone precursors of use in the method.
The present invention provides an efficient and inexpensive method for preparing ubiquinones and structural analogues of these essential molecules. Also provided are new compounds that are structurally simple and provide a convenient, efficient and inexpensive entry into the method of the invention.
Thus, in a first aspect, the present invention provides a compound according to Formula I: 
In Formula I, R1, R2 and R3 are independently selected C1-C6 alkyl groups, preferably methyl groups. R4 represents H or a protecting group. R5 is selected from branched, unsaturated alkyl, xe2x80x94C(O)H, and xe2x80x94CH2Y, in which Y is OR6, SR6, NR6R7, or a leaving group. R6 and R7 are independently selected from H and branched, unsaturated alkyl.
In a second aspect, the present invention provides a method for preparing a compound according to Formula IV: 
In Formula IV, each of R1, R2 and R3 is an independently selected C1-C6 alkyl group and the subscript n represents an integer from 0 to 13.
The method of the invention comprises, contacting a compound according to Formula V: 
with a compound according to Formula VI: 
In Formula V, R1, R2, R3 are as discussed above. Y is a leaving group and R4 is a protecting group. In Formula VI, L is an organometallic ligand; M is a metal; p is an integer from 1 to 5; and n is an integer from 0 to 13. Each of the organometallic ligands, L, can be the same or different.
The compounds according to Formulae V and VI are contacted in the presence of a catalyst that is effective at catalyzing coupling between a benzylic carbon atom, such as that in Formula V and an organometallic species according to Formula VI. The coupling of the compounds of Formulae V and VI, forms a compound according to Formula VII: 
The protecting group R4 is preferably removed from the compound according to Formula VII to produce a compound according to Formula VIII: 
The phenol is oxidized to the quinone of Formula IV, by contacting the compound according to Formula VIII with an oxidant.
Other objects and advantages of the invention will be apparent to those of skill in the art from the detailed description that follows.